A pharmacologically quantified and reproducible cat model of barbiturate dependency, which was developed in this laboratory, will be used for a continued study of barbiturate dependency and withdrawal. An initial aim is to apply this method in determining tolerance development, pharmacokinetics and the dependency liabilities associated with: (a) different levels of chronic pentobarbital dosing; (b) varying frequencies of administration and (c) different durations of dosing. The already defined maximal pentobarbital dependency will provide the reference for these studies. These same experimental variables will be considered in determining the tolerance, pharmacokinetic and withdrawal characteristics of other barbiturates and other CNS depressants, including ethanol and benzodiazepines. Using the cat dependency model, several possible drug therapies for withdrawal will be evaluated in whole animal and in an in vivo neuronal system. The effectiveness of benzodiazepines, a GABA modulator and steroid anesthetics will be explored. Studies of the effects of barbiturate dependency and withdrawal on adrenal corticoids and ACTH biofluid levels will be examined to determine the relationship between glucocorticoids and neuronal hyperexcitability during withdrawal. Neurophysiologic alterations during withdrawal will be examined in cat segmental reflex pathways. Our studies have uncovered certain synaptic vulnerabilities during barbiturate withdrawal. The neuronal loci and mechanisms of these will be investigated. Further, the neurophysiologic effects of ethanol and barbiturate withdrawals will be compared with respect to the neuronal loci involved and particular differences will be explored. Selective correction of neuronal disorders by potentially useful therapies will be tested. Studies of chronic barbiturate effects and withdrawal on the normal sleep cycle will be continued in the cat dependency model. This offers a new dimension for studies of dependency-withdrawal effects on sleep, because, in this model, the dependency withdrawal states have been quantitatively defined.